FOR THE PREPARATION THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Indian provisional patent applications no. IN 201641035046 filed on Oct 13, 2016; IN 201641041320 filed on Dec 2, 2016 and IN 201741006101 filed on Feb 21 , 2017, which are hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION The present invention relates generally to active pharmaceutical agents and method for their preparation and more specifically to solid dispersionsof trisodium sacubitril valsartanas well as a process for the preparation thereof. The present invention also relates to a method of preparation of trisodium sacubitril valsartan tablets.

BACKGROUND OF THE INVENTION Sacubitril valsartan, also known as LCZ696, isa co-crystallized complex ofvalsartan and sacubitril in a 1 : 1 molar ratio. Chemically, valsartan is known as (5)-3-methyl-2-(N-{ [2'-(2H- l,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butan oic acid and sacubitril is known as 4-{ [(25,4i?)-l-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentany l]amino}-4-oxobutanoic acid. LCZ696 consists of 6 valsartan anions, 6 sacubitril anions, 18 sodium cations, and 15 molecules of water. Sacubitril valsartanis marketed under the trade nameEntresto® by Novartis. The reduced formula of the sacubitril valsartan, as included in the Entresto® product, is shown below as Formula-I as a single valsartan molecule with a single sacubitril molecule together with three sodium anions and 2.5 water molecules.

Formula-I

Sacubitril is a neprilysin inhibitor and valsartan is an angiotensin II receptor blocker. Entresto® is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. PCT Publication No. W02007/056546 discloses a combination, more particularly, a supramolecular complex, of two active agents with different mechanisms of action, namely an angiotensin receptor antagonist and a neutral endopeptidase inhibitor. With respect to this disclosed combination, PCT Publication No. W02007/056546 is hereby incorporated by reference. PCT Publication No.WO2016/125123 discloses amorphous trisodium sacubitril valsartan.

PCT Publication Nos. WO2009/061713 and WO2017/012600 disclose solid pharmaceutical compositions of sacubitril/valsartan and pharmaceutically acceptable salts thereof.

PCT Publication Nos.WO2017/085573 and WO2017/037596 disclose an amorphous sacubitril- valsartan complex and solid dispersion with a pharmaceutically acceptable carrier. Very commonly, dosage forms of active ingredients include both the active ingredient as well as one or more pharmaceutically acceptable carriers or excipients. These excipients function to improve a variety of pharmaceutically relevant properties during manufacture of the dosage form as well as properties of the final dosage form itself. For example, excipients are carefully selected to improve process dynamics such as flowability, wettability, cohesiveness, and solubility of the API. Excipients may affect final dosage form properties such as bioavailability of the API, dissolution properties of the API (e.g., immediate, extended, continued release profiles), or stability in storage. Coordinating optimal addition and combination of excipients and active ingredients during manufacture is a complex and difficult process, requiring careful planning and execution to produce a dosage form that meets the requirements to be sold in the U.S.

Pre-prepared mixtures of active ingredients with excipients, commercially available as a "premix" or "solid dispersion" may ease some of this burden and difficulty of formulation. WO2017/085573 and WO2017/037596 disclose sacubitril/valsartan with a pharmaceutically acceptable carrier. In this case, it is likely that the solid dispersion with only one class of excipient (i.e., the carrier) would require addition of many other excipients in order to form the final dosage form, and complex planning and implementation would still be required.

The present invention provides an enhanced solid dispersion of trisodium sacubitril valsartan together with a pharmaceutically acceptable carrier and with one or more further excipients including anti-tacking agents, glidants, lubricants, and stabilizing agents. With the present invention, the pre-prepared mixture that contains an anti-taking agent, glidant, lubricant, stabilizing agent, or any combination thereof improves stability and handling of the solid dispersion when compared to mixtures without these agents. Further, inclusion of these agents may only require addition of one or two more ingredients to prepare a final dosage form, thus simplifying and streamlining the manufacture process.

Within the context of the present disclosure, trisodium [3-((lS, 3R)-l-biphenyl-4-ylmethyl-3- ethoxycarbonyl- 1 -butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl {2"-(tetrazol-5-ylate) biphenyl-4'-ylmethyl} amino) butyrate] will be referred to as "trisodium sacubitril valsartan." SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method of preparing a solid dispersion of trisodium sacubitril valsartan. In one embodiment, a solid dispersion of trisodium sacubitril valsartan may be prepared by a process which includes the following steps: a) dissolving amorphous trisodium sacubitril valsartan in a solvent to form a solution;

b) adding a solid dispersion agent to solution;

c) adding a processing aid; and

d) removing the solvent to isolate a solid dispersion of trisodium sacubitril valsartan.

Within the context of this embodiment, the solvent may be an alcohol solvent, a ketone solvent, an ester solvent, a chlorinated solvent, an ether solvent, water, or mixtures thereof.

Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. Examples of suitable ester solvents include, but are not limited to, methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate, and mixtures thereof. Examples of suitable chlorinated solvents include, but are not limited to, chloromethane, methylene dichloride, chloroform, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, and mixtures thereof.

In another aspect, the present invention provides a solid dispersion of trisodium sacubitril valsartan. In particularly useful embodiments, the solid dispersion of trisodium sacubitril valsartan includes a solid dispersion agent and an anti-tacking agent. Particularly useful solid dispersion agents include selected from the group consisting of hydroxypropyl methylcellulose, β-cyclodextrin, a polymer-blend based carriers, a silica based carrier, polyvinylpyrrolidone, and mixtures thereof. Particularly useful processing aids include stearic acid, magnesium stearate, sodium stearyl fumarate, and mixtures thereof.

Within the context of this embodiment, examples of suitable solid dispersion agents include, but are not limited to, saccharides, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e.g., polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, proprietary polymer blends, optionally substituted cyclodextrins, polysorbates, sorbitan monolaurate, silica-based carriers, and mixtures thereof.

Examples of suitable saccharides and polysaccharides include, but are not limited to, hydroxypropyl methylcellulose, carboxymethylcellulose and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof.

In a particularly useful embodiment, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate with a mass ratio of 60:40 is used as a solid dispersion agent.

Within the context of this embodiment, examples of suitable processing aids include, but are not limited to, lubricants, glidants, anti-tacking agents, stabilizing agents, and mixtures thereof.

Examples of suitable processing aids include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.

In another embodiment, a solid dispersion of trisodium sacubitril valsartan may be prepared by a process which includes the following steps: a) dissolving sacubitril and valsartan in a solvent to form a solution;

b) adding sodium hydroxide to the solution;

c) adding a solid dispersion agent;

d) adding a processing aid; and

e) removing the solvent to isolate a solid dispersion of trisodium sacubitril valsartan. Within the context of this embodiment, the solvent may be, for example, ethanol, ethyl acetate, methylene chloride, tetrahydrofuran, or mixtures thereof. Within the context of this embodiment, examples of suitable solid dispersion agents include, but are not limited to, saccharides, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e.g., polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, proprietary polymer blends, optionally substituted cyclodextrins, polysorbates, sorbitan monolaurate, silica-based carriers, and mixtures thereof.

Examples of suitable saccharides and polysaccharides include, but are not limited to, hydroxypropyl methylcellulose, carboxymethylcellulose and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof.

In a particularly useful embodiment, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate with a mass ratio of 60:40 is used as a solid dispersion agent.

Within the context of this embodiment, examples of suitable processing aids include, but are not limited to, lubricants, glidants, anti-tacking agents, stabilizing agents, and mixtures thereof.

Examples of suitable processing aids include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.

In another embodiment, a solid dispersion of trisodium sacubitril valsartan may be prepared by a process which includes the following steps: a) combining amorphous trisodium sacubitril valsartan, a solid dispersion agent, and a processing aid to form a mixture;

b) heating the mixture; c) cooling the mixture; and

d) further processing the obtained material to yield a solid dispersion of trisodium sacubitril valsartan.

Within the context of this embodiment, examples of suitable solid dispersion agentsinclude, but are not limited to, saccharides, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e.g., polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, proprietary polymer blends, optionally substituted cyclodextrins, polysorbates, sorbitan monolaurate, silica-based carriers, and mixtures thereof.

Examples of suitable saccharides and polysaccharides include, but are not limited to, hydroxypropyl methylcellulose, carboxymethylcellulose and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof. In a particularly useful embodiment, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate with a mass ratio of 60:40 is used as a solid dispersion agent.

Within the context of this embodiment, examples of suitable processing aids include, but are not limited to, lubricants, glidants, anti-tacking agents, stabilizing agents, and mixtures thereof.

Examples of suitable processing aids include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.

Within the context of the invention, the solid dispersions of trisodium sacubitril valsartan may be used to prepare pharmaceutical dosage forms, for example, a tablet or a capsule. BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing wherein: Figure 1 is apowder X-ray diffraction (PXRD) pattern ofa solid dispersion of trisodiumsacubitril valsartan with 40% HPMC and 10% stearic acid, prepared according toExample 16.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention providesa solid dispersion of trisodiumsacubitril valsartan together with a dispersion agent and aprocessing aid as well as processes for the preparation thereof.

Within the context of the invention, the term "about" when modifying an absolute measurement, such as time, mass, or volume, is meant to mean the recited value plus or minus 10% of that value. Within the context of the invention, the term "about" when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees. The solid dispersions of the trisodium sacubitril valsartan disclosed herein may be characterized as amorphous by X-ray powder diffraction (PXRD). Thus, samples of trisodium sacubitrilvalsartan solid dispersions, prepared by methods disclosed herein, were analyzed on a PanalyticalX'pertPro powder X-ray diffractometer equipped with goniometer of Θ/2Θ configuration and X'celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30 mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Figure 1 depicts a PXRD pattern obtained from one such analysis of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% stearic acid.

Another aspect of the present invention provides a process for the preparation of a solid dispersion of trisodium sacubitril valsartan. In one embodiment, a solid dispersion of trisodium sacubitril valsartan may be prepared by a process that includes the following steps: a) dissolving amorphoustrisodium sacubitril valsartan in a solvent to form a solution;

b) adding asolid dispersion agent to solution;

c) addinga processing aid; and

d) removing the solvent to isolate a solid dispersion of trisodium sacubitril valsartan. According to this embodiment,amorphous or crystalline trisodium sacubitril valsartanmay be dissolved in a solvent.Examples of suitable solvents include, but are not limited to, alcohol solvents, ketone solvents, ester solvents, chlorinated solvents, ether solvents, water, or mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methylethyl ketone, methylisobutyl ketone, and mixtures thereof. Examples of suitable ester solvents may be, but are not limited to,methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate, ormixtures thereof. Examples of chlorinated solvents include, but are not limited to, chloromethane, methylene dichloride, chloroform, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, and mixtures thereof. In certain embodiments of the present invention,water, ethanol, ethyl acetate, methylene dichloride, and miscible mixtures thereof were each found to be a particularly useful solvent.

Next, one or moresolid dispersion agentsmay be added to the solution.

Within the context of this embodiment, examples of suitable solid dispersion agents include saccharides and polysaccharides, polyvinylpyrrolidone,polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e.g., polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol (especially co-block polymers of polyethylene glycol and polypropylene glycol (such as those sold under the brand name Pluronic ^® , Tween ^® , Span ^® )), proprietary polymer blends (e.g., Eudragit ^® E PO, Ethocel™), cyclodextrins (e.g., a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β- cyclodextrin), polysorbates, sorbitan monolaurate, silica-based carriers, and mixtures thereof. Examples of suitable saccharides and polysaccharides include hydroxypropyl methylcellulose (HPMC, for example, those sold under the brand name Methocel™ (e.g., E3 Premium LV and E6 Premium LV) or Affinisol™ (e.g., HPMC-HME)), carboxymethylcellulose (CMC), and salts thereof (especially sodium and calcium salts), methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, and mixtures thereof.

Within the context of this embodiment, useful polyvinylpyrrolidones (or povidones) are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof. One of skill in the art would readily recognize different forms of povidone that would be useful and how each form may confer desired properties to a final product.

In particularly useful embodiments of the present invention, a copolymer of N-vinyl-2- pyrrolidone and vinyl acetate with a mass ratio of 60:40, for example, Plasdone S-630 or Kollidon ^® VA 64, is used as a solid dispersion agent.

Within the context of the present invention, the solid dispersion agent may be present in a solid dispersion of trisodium sacubitril valsartan at concentrations of between 15% w/w and 90% w/w, which includes 15-80%, 15-70%, 15-60%, 15-50%, 15-50%, 15-40%, 15-30%, 15-20%, 20- 90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40-50%, 50-90%, 50-80%, 50-70%, 50- 60%, 60-90%, 60-80%, 60-70%, 70-90%, 70-80%, and 80-90%.

Next, one or more processing aids may be added to the solution.

Within the context of this embodiment, examples of processing aids include lubricants, glidants, anti-tacking agents, and stabilizing agents. Specific examples include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.

Within the context of the present invention, the process enhancer may be present in the solid dispersion of trisodium sacubitril valsartan at a ratio ranging from 2% to 20%, which includes 2- 18%, 2-16%, 2-14%, 2-12%, 2-10%, 2-8%, 2-6%, 2-4%, 4-20%, 4-18%, 4-16%, 4-12%, 4-10%, 4-8%, 4-6%, 6-20%, 6-18%, 6-16%, 6-14%, 6-12%, 5-10%, 6-8%, 8-20%, 8-18%, 8-16%, 8- 14%, 8-12%, 8-10%, 10-20%, 10-18%, 10-16%, 10-14%, 10-12%, 12-20%, 12-18%, 12-16%, 12-14%, 14-20%, 14-18%, 14-16%, 16-20%, 16-18%, and 18-20%.

In particularly useful embodiments of the present invention, a solid dispersion is prepared with a combination of one or more of the following solid dispersion agents:

• hydroxypropyl methylcellulose (e.g., Ethocel™ E3 Premium LV, Ethocel™ E6 Premium L V, or Affinisol™ HPMC-HME 15LV);

• β-cyclodextrin;

• polymer-blend based carriers (e.g., Eudragit® E PO, Plasdone S-630);

• silica based carriers (e.g., Aeroperl® 300 or Syloid® AL-I FP);

• polyvinylpyrrolidone (e.g., povidone K30) and one or more of the following anti-tacking agents:

• stearic acid;

• magnesium stearate; and

• sodium stearyl fumarate.

Within the context of this embodiment, each of the first three steps a), b) and c) involving dissolution of trisodium sacubitril valsartan, the solid dispersion agent, and processing aid( "ingredients") may be carried out individually in any order, or two or more ingredients may be added simultaneously and dissolved simultaneously.

In particularly useful embodiments, a solid dispersion of trisodium sacubitril valsartan together with hydroxypropyl methylcellulose and steric acid is used. In such embodiments, hydroxypropyl methylcellulose (HPMC) and steric acid are present in the solid dispersion at a ratio of 1: 1, 5.5:4.5, 6:4, 6.5:3.5, 7:3, 7.5:2.5, 8:2, 8.5: 1.5, 9: 1, 9.5:0.5, 9.7:0.3, 9.8:0.2, or 9.9:0.1 (HPMC:stearic acid).

In other particularly useful embodiment, a solid dispersion of trisodium sacubitril valsartan together with hydroxypropyl methylcellulose and sodium stearyl fumarate is used. In such embodiments, hydroxypropyl methylcellulose (HPMC) and sodium stearyl fumarate are present in the solid dispersion at a ratio of 1: 1, 5.5:4.5, 6:4, 6.5:3.5, 7:3, 7.5:2.5, 8:2, 8.5: 1.5, 9: 1, 9.5:0.5, 9.7:0.3, 9.8:0.2, 9.9:0.1 (HPMOsodiumstearyl fumarate).

In other particularly useful embodiment, a solid dispersion of trisodium sacubitril valsartan together with Plasdone S6-30 and sodium stearyl fumarate is used. In such embodiments, Plasdone S6-30 and sodium stearyl fumarate are present in the solid dispersion at a ratio of 1: 1, 5.5:4.5, 6:4, 6.5:3.5, 7:3, 7.5:2.5, 8:2, 8.5: 1.5, 9: 1, 9.5:0.5, 9.7:0.3, 9.8:0.2, 9.9:0.1 (Plasdone S- 630:sodiumstearyl fumarate).

Next, the solvent may be removed to isolate a solid dispersion of trisodium sacubitril valsartan. This may be achieved by methods well known in the art, for example, by evaporation, distillation, spray drying, lyophilization, or agitated thin film drying.

In another aspect, trisodium valsartan sacubitril may be prepared in situ and not isolated prior to preparing a solid dispersion of trisodium valsartan sacubitril.

In one embodiment, this may be carried out by a process that includes the following steps: a) dissolving sacubitril and valsartan in a solvent to form a solution;

b) adding sodium hydroxide to the solution;

c) adding a solid dispersion agent;

adding a processing aid; and

e) removing the solvent to isolate a solid dispersion of trisodium sacubitril valsartan. According to this embodiment, sacubitril and valsartan may be dissolved in a solvent to form a solution. Examples of suitable solvents include, but are not limited to, ethanol, ethyl acetate, methylene chloride, tetrahydrofuran,and mixtures thereof.

Next, sodium hydroxide may be added to the solution. Within the context of this embodiment, sodium hydroxide is added to provide sodium cations to form the trisodium valsartan sacubitril complex. One of skill in the art would be able to calculate the amount of sodium hydroxide required based on the amount of sacubitril and valsartan used.

Next, one or moresolid dispersion agentsmay be added to the solution.

Within the context of this embodiment, examples of suitable solid dispersion agents include saccharides and polysaccharides, polyvinylpyrrolidone,polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates,polysorbates (e.g., Tween® 80), sorbitan monolaurate (e.g., Span® 20), vinyl pyrrolidone-vinyl acetate copolymers (e.g., Kollidon® and Plasdone™), polyalkylene glycols (for example polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (such as those sold under the brand name Pluronic ^® ), proprietary polymer blends (e.g., Eudragit ^® E PO, Ethocel™), silica or silicon dioxide (e.g., Aeroperl® 300, Syloid® AL-1 FP ), cyclodextrins (e.g., a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-P-cyclodextrin), and mixtures thereof. Examples of suitable saccharides and polysaccharides include hydroxypropyl methylcellulose (HPMC, for example, those sold under the brand name Methocel™ (e.g., E3 Premium LV and E6 Premium LV) or Affinisol™ (e.g., HPMC-HME)), carboxymethylcellulose (CMC), and salts thereof (especially sodium and calcium salts), methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, and mixtures thereof.

Within the context of this embodiment, useful polyvinylpyrrolidones (or povidones) are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof. One of skill in the art would readily recognize different forms of povidone that would be useful and how each form may confer desired properties to a final product.

One example of a suitable vinylpyrrolidone-vinyl acetate copolymer contains N-vinyl-2- pyrrolidone and vinyl acetate with a mass ratio of 60:40 (such as those sold under the brand name Kollidon and Plasdone (e.g., KollidonVA64 and Plasdone S-630).

Within the context of the present invention, the solid dispersion agent may be present in a solid dispersion of trisodium sacubitril valsartan at concentrations of between 15% w/w and 90% w/w, which includes 15-80%, 15-70%, 15-60%, 15-50%, 15-50%, 15-40%, 15-30%, 15-20%, 20- 90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40-50%, 50-90%, 50-80%, 50-70%, 50- 60%, 60-90%, 60-80%, 60-70%, 70-90%, 70-80%, and 80-90%.

Next, one or moreprocessing aids may be added.

Within the context of this embodiment, examples of processing aids include lubricants, glidants, anti-tacking agents, and stabilizing agents. Specific examples include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.

Within the context of the present invention, the process enhancer may be present in the solid dispersion of trisodium sacubitril valsartan at a ratio ranging from 2% to 20%, which includes 2- 18%, 2-16%, 2-14%, 2-12%, 2-10%, 2-8%, 2-6%, 2-4%, 4-20%, 4-18%, 4-16%, 4-12%, 4-10%, 4-8%, 4-6%, 6-20%, 6-18%, 6-16%, 6-14%, 6-12%, 5-10%, 6-8%, 8-20%, 8-18%, 8-16%, 8- 14%, 8-12%, 8-10%, 10-20%, 10-18%, 10-16%, 10-14%, 10-12%, 12-20%, 12-18%, 12-16%, 12-14%, 14-20%, 14-18%, 14-16%, 16-20%, 16-18%, and 18-20%. Finally, the solvent may be removed to isolate a solid dispersion of trisodium sacubitril valsartan. This may be carried out by methods well known in the art, for example, by evaporation, distillation, spray drying, lyophilization, or agitated thin film drying.

In another embodiment, a solid dispersion of trisodium sacubitril valsartan may be prepared by a process that includes the following steps: a) combining amorphous trisodium sacubitril valsartan, a solid dispersion agent, and a

processing aid to form a mixture;

b) heating the mixture;

c) cooling the mixture; and

d) further processing the obtained material to yield a solid dispersion of trisodium sacubitril valsartan.

Within the context of this embodiment, amorphous or crystalline trisodium sacubitril

valsartanmay first be mixed with one or moresolid dispersion agent and a processing aid to form a mixture. Within the context of this embodiment, examples of suitable solid dispersion agents include saccharides and polysaccharides, polyvinylpyrrolidone,polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, polysorbates (e.g., Tween® 80), sorbitan monolaurate (e.g., Span® 20), vinyl pyrrolidone-vinyl acetate copolymers (e.g., Kollidon® and Plasdone™), polyalkylene glycols (for example polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (such as those sold under the brand name Pluronic ^® ), proprietary polymer blends (e.g., Eudragit ^® E PO, Ethocel™), silica or silicon dioxide (e.g., Aeroperl® 300, Syloid® AL-1 FP ), cyclodextrins (e.g., a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-P-cyclodextrin), and mixtures thereof.

Examples of suitable saccharides and polysaccharides include hydroxypropyl methylcellulose (HPMC, for example, those sold under the brand name Methocel™ (e.g., E3 Premium LV and E6 Premium LV) or Affinisol™ (e.g., HPMC-HME)), carboxymethylcellulose (CMC), and salts thereof (especially sodium and calcium salts), methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, and mixtures thereof.

Within the context of this embodiment, useful polyvinylpyrrolidones (or povidones) are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof. One of skill in the art would readily recognize different forms of povidone that would be useful and how each form may confer desired properties to a final product.

One example of a suitable vinylpyrrolidone-vinyl acetate copolymer contains N-vinyl-2- pyrrolidone and vinyl acetate with a mass ratio of 60:40 (such as those sold under the brand name Kollidon ^® and Plasdone ^® (e.g., KollidonVA64 and Plasdone S-630).

Within the context of the present invention, the solid dispersion agent may be present in a solid dispersion of trisodium sacubitril valsartan at concentrations of between 15% w/w and 90% w/w, which includes 15-80%, 15-70%, 15-60%, 15-50%, 15-50%, 15-40%, 15-30%, 15-20%, 20- 90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40-50%, 50-90%, 50-80%, 50-70%, 50- 60%, 60-90%, 60-80%, 60-70%, 70-90%, 70-80%, and 80-90%.

Within the context of this embodiment, examples of processing aids include lubricants, glidants, anti-tacking agents, and stabilizing agents. Specific examples include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.

Within the context of the present invention, the process enhancer may be present in the solid dispersion of trisodium sacubitril valsartan at a ratio ranging from 2% to 20%, which includes 2- 18%, 2-16%, 2-14%, 2-12%, 2-10%, 2-8%, 2-6%, 2-4%, 4-20%, 4-18%, 4-16%, 4-12%, 4-10%, 4-8%, 4-6%, 6-20%, 6-18%, 6-16%, 6-14%, 6-12%, 5-10%, 6-8%, 8-20%, 8-18%, 8-16%, 8- 14%, 8-12%, 8-10%, 10-20%, 10-18%, 10-16%, 10-14%, 10-12%, 12-20%, 12-18%, 12-16%, 12-14%, 14-20%, 14-18%, 14-16%, 16-20%, 16-18%, and 18-20%. Particularly useful solid dispersion agents and process enhancers have a melting point of about 50 °C to about 200 °C. In particularly useful embodiments, the solid dispersion agent has a melting point of between about 60 °C and about 145 °C.

The mixture may then be heated. Within the context of this embodiment, heating will melt the mixture. This may be carried out by processes known in the art, for example, by hot melt extrusion. One of skill in the art would recognize appropriate parameters and conditions required to heat the mixture by hot melt extrusion. For example, in particularly useful embodiments, the following Zone temperatures are used: Zone 1: 60 °C; Zone 2: 90 °C; Zone 3: 100 °C; Exit temperature: 100 °C. In other particularly useful embodiments, the following Zone temperatures are used: Zone 1: 110 °C; Zone 2: 135 °C; Zone 3: 145 °C; Exit temperature: 160 °C.

In certain embodiments of the present invention, Plasdone S-630, Tween ^® 80, Span ^® 20, or mixtures thereof were found to be particularly useful solid dispersion agents.

Next, the heated mixture may be cooled, for example, to room temperature.

The mixture may then be further processed to provide a solid dispersion of trisodium sacubitril valsartan with properties as desired. For example, the mixture may be milled.

In particularly useful embodiments of the present invention, solid dispersions of trisodium sacubitril valsartan contain and are prepared using a vinylpyrrolidone-vinyl acetate copolymer, a polyvinylpyrrolidone, or a cyclodextrin as the solid dispersion agent.

In solid dispersions where a processing aidis used, it may be particularly useful to use an anti- tacking agent as said processing aid. In particularly useful embodiments of the present invention, a solid dispersion is prepared with a combination of one or more of the following solid dispersion agents:

• hydroxypropyl methylcellulose (e.g., Ethocel™ E3 Premium LV, Ethocel™ E6 Premium L V, or Affinisol™ HPMC-HME 15LV);

• β-cyclodextrin;

• polymer-blend based carriers (e.g., Eudragit® E PO, Plasdone S-630);

• silica based carriers (e.g., Aeroperl® 300 or Syloid® AL-I FP);

• polyvinylpyrrolidone (e.g, povidone K30) and one or more of the following anti-tacking agents:

• stearic acid;

• magnesium stearate; and

• sodium stearyl fumarate.

In particularly useful embodiments of the present invention where the solid dispersion agent is hydroxypropyl methylcellulose, one of magnesium stearate, sodium stearyl fumarate, or stearic acid is often used. In particularly useful embodiments, magnesium stearate or sodium stearyl fumarate is combined with hydroxypropyl methylcellulose to prepare a solid dispersion of trisodium sacubitril valsartan.

The solid dispersions disclosed herein may be combined with further pharmaceutically acceptable excipients to prepare a final dosage form, for example, a solid oral dosage form.

As used herein and within the context of the present invention,pharmaceutically acceptable excipientsare inert ingredients that are used in the manufacture of solid oral dosage forms and that are combined with an active ingredient, a pre-prepared mixture (e.g., a solid dispersion) containing the active ingredient during dosage formulation. Examples of categories of pharmaceutically acceptable excipients include, but are not limited to, solid dispersion agents, anti-tacking agents, glidants, lubricants, stabilizing agents,binders, disintegrants, fillers, and diluents. Examples of pharmaceutically acceptable binders include, but are not limited to, starches, celluloses, and derivatives thereof. Examples of celluloses and their derivatives include hydroxypropyl methylcellulose, carboxymethylcellulose, and salts thereof (especially sodium and calcium salts), methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (high or low substituted), hydroxylethyl cellulose, microcrystalline cellulose, sucrose, dextrose, corn syrup, polysaccharides, gelatin, and mixtures thereof. In particularly useful embodiments, low substituted hydroxypropyl cellulose is used. Within the context of the present invention, the binder may be present in the final dosage form at a concentration from about 1% to 10 % w/w, which includes 1-9%, 1-8%, 1-7%, 1-6%, 1-5%, 1- 4%, 1-3%, 1-2%, 2-10%, 2-9%, 2-8%, 2-7%, 2-6%, 2-5%, 2-4%, 2-3%, 3-10%, 3-9%, 3-8%, 3- 7%, 3-6%, 3-5%, 3-4%, 4-10%, 4-9%, 4-8%, 4-7%, 4-6%, 4-5%, 5-10%, 5-9%, 5-8%, 5-7%, 5- 6%, 6-10%, 6-9%, 6-8%, 6-7%, 7-10%, 7-9%, 7-8%, 8-10%, 8-9%, and 9-10% w/w.In particularly useful embodiments, the binder is present at a concentration of about 3% to 5% w/w.

Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches clays, celluloses, alginates, gums (e.g., guar), cross-linked polymers (e.g., crospovidone such as Polyplasdone XL andPolyplasdoneXL-10), croscarmellose sodium, (e.g., AC-DI- SOL),croscarmellose calcium, soy polysaccharides, and mixtures thereof. In particularly useful embodiments, crospovidone is used as a disintegrant. Within the context of the present invention, the disintegrant may be present in the final dosage form at a concentration from about 1% to 10 % w/w which includes 1-9%, 1-8%, 1-7%, 1-6%, 1-5%, 1-4%, 1-3%, 1-2%, 2-10%, 2- 9%, 2-8%, 2-7%, 2-6%, 2-5%, 2-4%, 2-3%, 3-10%, 3-9%, 3-8%, 3-7%, 3-6%, 3-5%, 3-4%, 4- 10%, 4-9%, 4-8%, 4-7%, 4-6%, 4-5%, 5-10%, 5-9%, 5-8%, 5-7%, 5-6%, 6-10%, 6-9%, 6-8%, 6- 7%, 7-10%, 7-9%, 7-8%, 8-10%, 8-9%, and 9-10% w/w. In particularly useful embodiments, the disintegrant is present at a concentration of about 3% to 5% w/w. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, sodium stearyl fumarate, and mixtures thereof. In particularly useful embodiments, magnesium stearate is used as a lubricant and colloidal silica is used as a glidant.

Within the context of the present invention, the lubricant may be present in the final dosage form at a concentration from aboutO.01% to 5% w/w, which also includes 0.05-5%, 0.5-4%, 0.5-3%, 0.5-2%, 0.5-1%, 1-5%, 1-4%, 1-3%, 1-2%, 2-5%, 2-4%, 2-4%, 3-5%, 3-4%, and 4-5%. Inparticularly useful embodiments, the lubricant is present at a concentration of about 0.5% to 1 % w/w. Within the context of the present invention, the glidant may be present in the final dosage form at a concentration from aboutO.01% to 5% w/w, which also includes 0.05-5%, 0.5- 4%, 0.5-3%, 0.5-2%, 0.5-1%, 1-5%, 1-4%, 1-3%, 1-2%, 2-5%, 2-4%, 2-4%, 3-5%, 3-4%, and 4- 5%. Inparticularly useful embodiments, the glidant is present at a concentration of about 0.5% to 1 % w/w.

Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, and mixtures thereof. In particularly useful embodiments, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, or mixtures thereof are used. In other particularly useful embodiments, microcrystalline cellulose is used.Within the context of the present invention, the filler/diluent may be present in the final dosage form at a concentration from aboutl% to 10% which includes 1-9%, 1-8%, 1-7%, 1-6%, 1-5%, 1-4%, 1-3%, 1-2%, 2-10%, 2-9%, 2-8%, 2-7%, 2-6%, 2-5%, 2-4%, 2-3%, 3-10%, 3-9%, 3-8%, 3-7%, 3-6%, 3-5%, 3-4%, 4-10%, 4-9%, 4-8%, 4-7%, 4-6%, 4-5%, 5-10%, 5-9%, 5-8%, 5-7%, 5-6%, 6-10%, 6-9%, 6-8%, 6-7%, 7-10%, 7-9%, 7-8%, 8-10%, 8-9%, and 9-10% w/w. In particularly useful embodiments, the filler/diluent is present at a concentration of about 5% to 7% w/w.

Solid oral dosage forms, for example, tablets or capsules, may be further coated with suitable coating agents by methods well-known to a person skilled in the art. Examples of suitable coating agents include, but are not limited to, Opadry AMB-II, Opadry white, Opadry yellow, Opadry red, Opadry black, and Aquarius. In one embodiment of the present invention, a solid dosage form of trisodium sacubitril valsartan may be prepared by mixing a solid dispersion of trisodium sacubitril valsartan with one or more pharmaceutical excipients as outlined above and compressing the mixture into tablets, which may then be optionally coated. In another embodiment of the present invention, a solid dosage form of trisodium sacubitril valsartan may be prepared by mixing amorphous sacubitril valsartan with pharmaceutical excipients and compressing the mixture into tablets, which may then be optionally coated.

Amorphous trisodium sacubitril valsartan may be prepared by processes disclosed in PCT PublicationNo. WO 2016/125123. The tablet composition of present invention can be prepared by any known techniques known in the art, for example, direct compression, dry granulation, and roller compression.

Certain advantages may be realized with the solid dispersions containing trisodium sacubitril valsartan together with a solid dispersion agent and an anti-tacking agent. For example, the stability of solid dispersions that include the anti-tacking agent is improved when compared to similar solid dispersions prepared without anti-tacking agents, which tend to be highly hygroscopic. Hygroscopic formulations become gummy and more viscous upon storage in an environment that contains water vapor, significant chemical degradation of the formulation often occurs. In solid dispersions that contain an anti-tacking agent, PXRD and stability data indicate that chemical degradation is avoided. To illustrate the enhanced properties of the solid dispersions of trisodium sacubitril valsartan and dosage forms prepared therefrom, stability during storage was thus measured by PXRD and HPLC.

PXRD analyses were performed previously described. HPLC analyses were performed by routine methods well known in the art, for example, on anXB ridge C18 column (150 mm x 4.5 mm, 3 μπι), using a UV detector set at 210 nm with a column oven temperature of about 30 °C. A flow rate of 1.5 ml/min with an injection volume of 10 μL· may be used, with a run time of approximately 45 minutes. The mobile phase was a ratio of 95:50:25 (by volume) acetonitrile : water : tetrahydrofur an .

The trisodium sacubitril valsartan solid dispersions and pharmaceutical tablet compositions prepared therefrom according to the present invention contain trisodium sacubitril valsartan at a HPLC purity of more than 99%.

As used herein, a compound or pharmaceutical composition is considered "stable" when the HPLC purity of the compound or solid dispersion changes by less than about 1 % when stored at 5 ± 3 °C and/or at 25 °C/60% and 40 °C/75% relative humidity (RH).

The stability of a solid dispersions of trisodium sacubitrilvalsartan with 18% w/w hydroxypropyl methylcellulose and 2% w/w sodium stearyl fumarate as well as 18% Plasdone S-630 and 2% w/w sodium stearyl fumarate were tested, along with tablet compositions prepared therefrom by storing the samples at 40 °C/75% relative humidity (RH) and at 25 °C/60% relative humidity (RH) conditions for 3 months. The samples were analyzed for moisture content (MC), a stable PXRD pattern over time (i.e., remains amorphous), and HPLC for final purity assessment. Results of such testing revealed that no significant chemical degradation and no change in PXRD pattern occurred when samples were stored for 3 months at 40 °C/75% and at 25 °C/60% relative humidity (RH) conditions. This data is shown below in Table 1 (solid dispersions) and Tables 2 and 3 (tablet compositions). Within the context of these tables, TSV stands for trisodium sacubitril valsartan, SSF stands for sodium stearyl fumarate, and A stands for amorphous. Table 1

at 25 °C/60% RH

Initial 6.84 99.91 A 1.91 99.86 A

15 days 7.88 99.9 Stable 5.21 99.91 Stable

1 months 8.21 99.9 Stable 6.45 99.89 Stable

2 months 7.46 99.91 Stable 5.07 99.89 Stable

3 months 6.86 99.9 Stable 7.42 99.91 Stable

Table 2

Table 3

15 days 10.55 99.91 Stable 9.99 99.91 Stable

1 months 3.1 99.89 Stable 4.29 99.88 Stable

2 months 4.53 99.91 Stable 4.53 99.91 Stable

3 months 5.79 99.87 Stable 5.16 99.9 Stable at 25 °C/60% RH

Initial 5.7 99.92 A 4.92 99.92 A

15 days 10.03 99.92 Stable 10.51 99.91 Stable

1 months 3.34 99.89 Stable 3.81 99.85 Stable

2 months 5.0 99.91 Stable 5.44 99.93 Stable

3 months 4.54 99.91 Stable 5.08 99.9 Stable

Dosage forms that include the trisodium sacubitril valsartan and solid dispersions thereof may be useful for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction. In particularly useful embodiments, oral dosage forms include sacubitril from about 24 mg to about 97 mg. In particularly useful embodiments, oral dosage forms include valsartan from about 26 mg to about 103 mg. In particularly useful embodiments, oral dosage forms 24 mg of sacubitril and 26 mg of valsartan; 49 mg of sacubitril and 51 mg of valsartan; or 97 mg of sacubitril and 103 mg of valsartan. The following examples are provided to illustrate the process of the present invention. They are, however, not intended to limit the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

EXAMPLES:

Example 1: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w HPMC

Amorphous trisodium sacubitril valsartan (8 g) was dissolved in water (40 ml) at 25±2°C. In another flask,hydroxypropyl methylcellulose (8 g) was dissolved in water (160 ml) at 25±2°C.The two solutions were combined to make one solution which was then filtered through Hyflo to remove any undissolved particulate. The solution was then subjected to spray drying in laboratory spray dryer (Model Buchi-290) with inlet temperature at 100°C and 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w HPMC.

Example 2: Preparation of solid dispersion of trisodium sacubitril valsartan with 50% Plasdone S-630

Amorphous trisodium sacubitril valsartanamorphous form (8 g) and Plasdone S-630 (8 g) were dissolved in ethanol (80 ml) at 25±2°C. The resulting clear solution was filtered through Hyfloto remove any undissolved particulate. The solution was then subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 80 °C and 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w Plasdone S-630.

Example 3: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w povidone K30

Amorphous trisodium sacubitril valsartan (8 g) and Povidone K30 (8 g) were dissolved in ethanol (80 ml) at 25±2°C. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate. The solution was then subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 80 °C and with 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w povidone K30.

Example 4: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w β-cyclodextrin β-cyclodextrin (10 g) was dissolved in a mixture of water (150 ml) and ethanol (50 ml) at 75±5 °C. The solution was then cooled to 25±5°C and amorphous trisodium sacubitril valsartan (10 g) was added. The mixture was stirred for 15-30 minutes and the resulting solution was filtered through Hyflo to remove any undissolved particulate. The solution was then subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100°C and with 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w β-cyclodextrin. Example 5: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w hydroxypropyl-P-cyclodextrin

Amorphous trisodium sacubitril valsartan (10 g) and hydroxypropyl-P-cyclodextrin (10 g) were dissolved in ethanol (200 ml) at 65±5°C. The resulting solution was filtered through Hyflo to remove any undissolved particulate and the filtrate was subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 80 °C and with 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w hydroxypropyl-P-cyclodextrin.

Example 6: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% HPMC-HME Amorphous trisodium sacubitril valsartan (9 g) was dissolved in ethanol (25 ml) at 25±2°C. In another flask, hydroxyl propyl methylcellulose (HPMC-HME 15LV, 9 g) was dissolved in ethanol (200 ml) at 75±5°C and cooled to 25±2°C. The two solutions were combined, filtered through Hyflo to remove any undissolved particulate, and the filtrate was subjected to spray drying in laboratory spray dryer (Model Buchi-290) with inlet temperature at 80°C and 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w HPMC.

Example 7: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% Plasdone S-630 by hot melt-extrusion

Amorphous trisodium sacubitril valsartan (10 g) andPlasdone S-630 (10 g) were passed through a 40mesh sieve and subjected to melt extrusion on hot melt extruder instrument (Make: Leistritz, model: Nanol6) with following experimental conditions: Zone-1 temperature: 110°C, Zone-2 temperature: 135°C, Zone-3 temperature: 145°C and exit zone temperature of 160°C. The product was milled the product at 25±2°C. Characterization by PXRD showed it to beamorphous.

Example 8: Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% w/w Plasdone S-630 and 10% Tween 80 by hot melt-extrusion A mixture of amorphous trisodium sacubitril valsartan (10 g), Plasdone S-630 (8 g), and Tween 80 (2 g) was prepared. The mixture was then milled and passed through 40mesh sieve. The homogeneous mixture was then subjected to melt extrusion on hot melt extruder instrument (Make: Leistritz, model: Nanol6) with following experimental conditions: Zone-1 temperature: 60°C, Zone-2 temperature: 90°C, Zone-3 temperature: 100 °C and exit zone temperature of 100 °C. The product obtained was milled at 25±2°C. Characterization by PXRD revealed the final product to be amorphous.

Example 9: Preparation of a solid dispersion of trisodium sacubitril valsartanwith 40% w/w Plasdone S-630 and 10% Span 20 by hot melt-extrusion A mixture of amorphous trisodium sacubitril valsartan amorphous form (10 g), Plasdone S-630 (8 g), and Span 20 (2 g) was prepared. The mixture was milled and passed through 40mesh sieve. The homogeneous mixture was subjected to melt extrusion on hot melt extruder instrument (Make: Leistritz, model: Nanol6) with following experimental conditions: Zone-1 temperature: 60°C, Zone-2 temperature: 90°C, Zone-3 temperature: 100°C and exit zone temperature of 100°C. The product obtained was milled at 25±2°C and characterizedby PXRD as amorphous.

Example 10: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w Eudragit E PO

Sacubitril (25 g) and valsartan (26.4 g) were dissolved in ethanol (150 ml). In another flask,sodium hydroxide (7.25 g) dissolved in water (20 mL) then diluted with ethanol (50 ml). The sodium hydroxide solution was added to the above solution of sacubitril and valsartan to form a reaction mass, which was stirred for 90-120 minutes at 25-30°C and concentrated under vacuum. Traces of water were removed using ethanol (3x75 ml) until the moisture level of the resulting residue dropped to less than 0.5%. Ethyl acetate (150 ml) was added to the residue and the mixture was stirred at 40-45 °C until a clear solution was formed. The solution was then filtered through a micron filter, cooled to 25-35 °C,andEudragit E PO (50 g) was added. The solution was then concentrated. Isopropyl ether (50 ml) was addedthen stripped off completely. Isopropyl ether (250 ml) was added again to the flask and the mixture was stirred at 25-30°C for 60-90 minutes then filtered. The solid was washed with isopropyl ether (50 ml) then dried under vacuum to get 98g material, which was characterized by PXRD as amorphous.

Example 11: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w Ethocel Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml). In another, flask sodium hydroxide (1.425g) was dissolved in water (4 ml) then diluted with ethanol (10 ml). The sodium hydroxide solution was added to the above clear solution of sacubitril and valsartan to form a reaction mass, which was stirred for 30 minutes at 25-30°C and concentrated under vacuum. Traces of water were removed using ethanol(3xl5 ml) until the moisture level of the residue was to less than 0.5%. Ethyl acetate (30 ml) was added to the residue and the mixture was stirred at 40-45 °C until a clear solution was formed, which was then filtered through micron filter and cooled to 25-35°C. Ethocel (10 g) was added and the mixture was stirred for 30 minutes followed by complete concentration under vacuum maintaining the temperature below 60°C. Isopropyl ether (10 ml) was added and then stripped off completely. Isopropyl ether (50 ml) was again added to the flask and stirred at 25-30°C for 30 minutes. The solution was filtered and the obtained solid waswashed with isopropyl ether (10 ml). The solid was then dried under vacuum to get 19.6 g material, which was then characterized by PXRD asamorphous.

Example 12: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% Aeroperl 300 Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml). In another flask,sodium hydroxide (1.425 g) was dissolved in water (4 ml) then diluted with ethanol (10 ml). This sodium hydroxide solution was then added to the above clear solution of sacubitril and valsartan to form a reaction mass. The reaction mass was stirred for 30 minutes at 25-30°C andconcentrated under vacuum. Traces of water were removed using ethanol(3xl5 ml) until the moisture level of the residue fell below 0.5%. Ethyl acetate (30ml) was added to the residue and the mixture was stirred at 40-45 °C until a clear solution was formed, which was then filtered through a micron filter. The solution was then cooled to 25-35°C and Aeroperl 300 (10 g) was added. The resulting mixture was and stirred for 30 minutes followed by complete concentration under vacuum maintaining them temperature below 60°C. Isopropyl ether (10 ml) was added then stripped off completely. Isopropyl ether (50 ml) was again added and the mixture was stirred at 25-30°C for 30 minutes. The solution was filtered and the obtained solid was washed with isopropyl ether (10 ml). The solid was dried under vacuum to get 19g material, which was characterized by PXRD as amorphous.

Example 13: Preparation of a solid dispersionof trisodium sacubitril valsartan with 50% w/w Aeroperl

Sacubitril (10 g) and valsartan (10.6 g) were dissolved in ethanol (60 ml). In another flask,sodium hydroxide (2.9 g) was dissolved in water (8 ml) then diluted with ethanol (20 ml). Thesodium hydroxide solution was added to the above clear solution of sacubitril and valsartan to form a reaction mass. The reaction mass was stirred for 90 minutes at 25-30°C then concentrated under vacuum maintaining the temperature below 60°C. Methylene dichloride (150 ml) was charged to the reaction mass and water was removed azeotropically from the reaction mass until the moisture content dropped below 0.20%. The reaction mass was cooled to 25-30°C and Aeroperl 300 (20 g) was added. Methylene dichloride was then distilled off completely. Traces of water were removed using isopropyl ether (20 ml), maintaining the temperature below 50°C. Isopropyl ether (100 ml) was again added to the flask and the solution was stirred at 25- 30°C for 30 minutes and filtered. The obtained solid was washed with isopropyl ether (10 ml). The filtered material was dried under vacuum to get 38 g material, which was characterized by PXRD as amorphous.

Example 14: Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% Syloid AL-I FP

Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml). In another flask,sodium hydroxide (1.425 g) was dissolved in water (4 ml) then diluted with ethanol (10 ml). Thesodium hydroxide solution was added to the above clear solution of sacubitril and valsartan to form a reaction mass. The reaction mass was stirred for 30 minutes at 25-30°C then concentrated under vacuum. Traces of water were removed using ethanol (3x15 ml) until the moisture level of the residue dropped below 0.5%. Ethyl acetate (30 ml) was added to the residue and the resulting mixture was stirred at 40-45 °C until it became clear solution. The solution was then filtered through micron filter, cooled to 25-35°C, and Syloid AL-I FP (10 g) was added. The mixture was stirred for 30 minutes then concentrated completely under vacuum, maintaining the temperature below 60°C. Isopropyl ether (10 ml) was charged to the mixturethen stripped off completely. Isopropyl ether (100 ml) was again charged to the flask and the resulting solution was stirred at 25-30°C for 30 minutes. The solution was then filtered and the obtained solid was washed with isopropyl ether (10 ml). The solid was dried under vacuum to get 19 g material, which was characterized by PXRD as amorphous.

Example 15:Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10 % stearic acid

Amorphous trisodium sacubitril valsartan (5 g), hydroxypropyl methylcellulose (E6 Premium LV) (4g) and stearic acid (lg) were suspended in mixture of water (60 ml) and ethanol (120 ml) at 25-30°C. The reaction mass was heated to 75-85°C to obtain aclear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate. The clear solution was re -heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100 °C and a flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitril valsartan with 40% w/w HPMC and 10% w/w stearic acid.

Example 16: Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% stearic acid

Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml). In a separate flask,sodium hydroxide (1.425g) was dissolved in water (4ml) then diluted with ethanol (10ml). This sodium hydroxide solution was added to the above clear solution of sacubitril and valsartan to form a reaction mass. The reaction mass was stirred for 30 minutes at 25-30°C then concentrated under vacuum. Traces of water were removed using ethanol (3x15ml) until the moisture level of the resulting residue dropped below 0.5%. Ethyl acetate (30ml) was added to the residue and the mixture was stirred at 40-45 °C to obtain a clear solution, which was then filtered through a micron filter. The solution was then cooled to 25-35°C and HPMC E6 (8 g) andstearic acid (2g) were added. The mixture was stirred for 30 minutes thenconcentrated completely under vacuum maintaining the temperature below 60°C. Isopropyl ether (10ml) was charged to the mixture then stripped off completely. Isopropyl ether (50ml) was again charged to the flask and the mixture was stirred at 25-30 °C for 30 minutes. The solution was filtered and the obtained solid was washed with isopropyl ether (10 ml). The solid was then dried under vacuum to get 19.2g material, which was characterized by PXRD as amorphous.

Example 17: Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% sodium stearyl fumarate

Amorphous trisodium sacubitril valsartan (5 g), hydroxypropyl methylcellulose (E6 Premium LV) (4g) and sodium stearyl fumarate (lg) were suspended in a mixture of water (60 ml) and ethanol (120 ml) at 25-30°C. The reaction mass was heated to 75-85°C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate. The clear solution was re -heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100 °C and flow rate of 5 ml/minute to yield a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% sodium stearyl fumarate.

Example 18:Preparation of a solid dispersion of trisodium sacubitril valsartan with 45% HPMC and 5% magnesium stearate

Amorphous trisodium sacubitril valsartan (5 g) was dissolved in ethyl acetate (50 ml). The reaction mass was heated to 50-55°C. Hydroxy propyl methylcellulose (4.5 g) and magnesium stearate (0.5g) were charged to the solution.The reaction mass was stirred at 50-55 °C for 15-30 minutes. The reaction mass was concentrated under vacuum maintaining the temperature below 60°C. Traces of water were removed using isopropyl ether (50 ml). Isopropyl ether (50 ml) was again charged to the reaction mass which was cooled to 25-30°C then stirred for 30 minutes. The reaction mass was filtered and the obtained solid was washed with isopropyl ether (10 ml). The solid material was dried in under vacuum oven at 70-75 °C to get 9.8 g of a solid dispersion of trisodium sacubitril valsartan with 45% HPMC and 5% magnesium stearate. Example 19: Preparation of a solid dispersion of trisodium sacubitril valsartan with 45% HPMC and 5% sodium stearyl fumarate

Amorphous trisodium sacubitril valsartan (5 g) was dissolved in ethyl acetate (50 ml). The reaction mass was heated at 50-55 °C to dissolve the solids. Hydroxypropyl methylcellulose (4.5 g) and sodium stearyl fumarate (0.5 g) were charged to the solution which was then stirred at 50-55 °C for 15-30 minutes. The reaction mass was concentrated under vacuum maintaining the temperature below 60°C. Traces of water were removed using isopropyl ether (50 ml). Isopropyl ether (50 ml) was again charged to the reaction mass which was then cooled to 25- 30 °C and stirred for 30 minutes. The reaction mass was then filtered and the obtained solid was washed with isopropyl ether (10 ml).The solid was then dried in under vacuum oven to get 9.6 g of a solid dispersion of trisodium sacubitril valsartan with 45% HPMC and 5% sodium stearyl fumarate.

Example 20: Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% sodium stearyl fumarate Amorphous trisodium sacubitril valsartan (25g), hydroxypropyl methylcellulose (E6 Premium LV, 20g), and sodium stearyl fumarate (5g) were suspended in a mixture of water (300 ml) and ethanol (600 ml) at 25-30°C. The reaction mass was heated to 75-85°C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with mixture of water and ethanol (1:2 ratio, 50 ml). The clear solution was re-heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100 °C and flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% sodium stearyl fumarate.

Example 21 Preparation of a solid dispersion of trisodium sacubitril valsartan with 18% HPMC and 2% sodium stearyl fumarate Amorphous trisodium sacubitrilvalsartan (50g), hydroxypropylmethylcellulose (E6 Premium LV, 11.25g) and sodium stearyl fumarate (1.25g) were suspended in a mixture of water (300 ml) and ethanol (900 ml) at 25-30 °C. The reaction mass was heated to 75-85 °C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with mixture of water and ethanol (1:2 ratio, 50 ml). The clear solution was re-heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100°C and a flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitrilvalsartan with 18% HPMC and 2% sodium stearyl fumarate. Example 22: Preparation of a solid dispersion of trisodium sacubitril valsartan with 18% HPMC and 2% sodium stearyl fumarate

Amorphous trisodium sacubitril valsartan (25g), hydroxypropyl methylcellulose (E3 Premium LV, 5.625g) and sodium stearyl fumarate (0.625g) were suspended in a mixture of water (150 ml) and ethanol (450 ml) at 25-30°C. The reaction mass was heated to 75-85°C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with mixture of water and ethanol (1:2 ratio, 50 ml). The clear solution was re-heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100°C and flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitril valsartan with 18% HPMC and 2% sodium stearyl fumarate. Example 23: Preparation of a solid dispersion of trisodium sacubitril valsartan with 18% Plasdone S-630 and 2% sodium stearyl fumarate

Amorphous trisodium sacubitrilvalsartan (50g), Plasdone S-630 (11.25g), and sodium stearyl fumarate (1.25g) were dissolved in ethanol (950 ml) at 75-85°C. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with ethanol (50 ml). The clear solution was re-heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 70 °C and flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitrilvalsartan with 18% Plasdone S-630 and 2% sodium stearyl fumarate.

Example 24: Preparation of a solid dispersion of trisodium sacubitril valsartan with 26.7% HPMC and 7% sodium stearyl fumarate

Amorphous trisodium sacubitrilvalsartan (5g), hydroxypropyl methylcellulose (E6 Premium LV) (2g) and sodium stearyl fumarate (0.5g) were suspended in a mixture of water (60 ml) and ethanol (133 ml) at 25-30°C. The reaction mass was heated to 70-75°C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with mixture of water and ethanol (1:2 ratio, 15 ml). The clear solution was re-heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100°C and flow rate of 5ml/minute to yielda solid dispersion of trisodium sacubitrilvalsartan with 26.7% HPMC and 7% sodium stearyl fumarate.

Example 25: Tablet formulation containing 200mg equivalent of sacubitril-valsartan prepared using a solid dispersion of trisodium sacubitril valsartan with 18% HPMC and 2% sodium stearyl fumarate

Unit composition: (With Opadry AMB-II film coating tablet)

Brief Manufacturing Process:

S.No Operations

1 A solid dispersion of trisodium sacubitril valsartan amorphous, microcrystalline cellulose, low substituted hydroxypropylcellulose, crospovidone, and colloidal silicon dioxide were sifted together through a suitable sieve.

2 Magnesium stearate (intragranular) and magnesium stearate (extragranular) were sifted separately through a suitable sieve.

3 The sifted material in Step No. 1 was charged into a low shear bin blender and blended for a suitable time.

4 Magnesium stearate (intragranular) of Step No.2 was added to Step 3 blend and blended for a suitable time. 5 Step No.4 blend was compacted using roll compactor.

6 Step No.5 compacts were milled through a suitable screen.

7 The milled material of Step No. 6 was sifted through ASTM 25 mesh (710 microns) and the retained portion and passing portion were collected separately.

8 Magnesium stearate (extragranular) of Step no. 2 was added to the blended material of Step no.7 and blended for a suitable time.

9 Crospovidone and colloidal silicon dioxide were added to the material of Step no.8 and blended for a suitable time.

10 The lubricated blend was compressed into tablets.

11 A coating dispersion of PVA-based coating (Opadry AMB-II) white in purified water was prepared and the tablets were coated in a perforated coating pan.

Example 26: Tablet formulation containing 200 mg equivalent of sacubitril-valsartan prepared using a solid dispersion of trisodium sacubitril valsartan with 18% Plasdone S- 630 and 2% sodium stearyl fumarate

Unit composition: (With Opadry AMB-II film coating tablet)

2 Microcrystalline Cellulose (PH 112) 18.00 5.81

3 Low-substituted

10.00 3.23 hydroxypropylcellulose

4 Crospovidone (PP-XL) 12.00 3.87

5 Magnesium stearate 2.00 0.65

6 Colloidal silicon dioxide 2.00 0.65

Extragranular

7 Crospovidone (PP-XL) 12.00 3.87

8 Magnesium stearate 2.00 0.65

9 Colloidal silicon dioxide 2.00 0.65

Core Tablet Weight 310.00 100.00

Coatin R

10 Aquarius 12.4 4.0

Total tablet weight 322.4 3-5

Brief Manufacturing Process:

Example 27: Tablet formulation containing 200 mg equivalent of sacubitril-valsartan prepared using an amorphous trisodium sacubitril valsartan

Unit composition: (with PVA based film coating tablet)

Brief Manufacturing Process: